tbuckley/cabot-search huggingface dataset:
Addressing antimicrobial resistance with the IDentif.AI platform: Rapidly optimizing clinically actionable combination therapy regimens against nontuberculous mycobacteria
Authors: Devika Mukherjee, Peter Wang, Lissa Hooi, Vedant Sandhu, Kui You, Agata Blasiak, Edward Kai-Hua Chow, Dean Ho, Pui Lai Rachel Ee
Journal: Theranostics (2022)

Background: Current standard of care (SOC) regimens against nontuberculous mycobacteria (NTM) usually result in unsatisfactory therapeutic responses, primarily due to multi-drug resistance and antibiotic susceptibility-guided therapies.In the midst of rising incidences in NTM infections, strategies to develop NTM-specific treatments have been explored and validated.Methods: To provide an alternative approach to address NTM-specific treatment, IDentif.AI was harnessed to rapidly optimize and design effective combination therapy regimens against Mycobacterium abscessus (M.abscessus), the highly resistant and rapid growth species of NTM.IDentif.AI interrogated the drug interaction space from a pool of 6 antibiotics, and pinpointed multiple clinically actionable drug combinations.IDentif.AI-pinpointed actionable combinations were experimentally validated and their interactions were assessed using Bliss independence model and diagonal measurement of n-way drug interactions.Results: Notably, IDentfi.AI-designed 3-and 4-drug combinations demonstrated greater %Inhibition efficacy than the SOC regimens.The platform also pinpointed two unique drug interactions (Levofloxacin (LVX)/Rifabutin (RFB) and LVX/Meropenem (MEM)) that may serve as the backbone of potential 3-and 4-drug combinations like LVX/MEM/RFB, which exhibited 58.33±4.99%Inhibition efficacy against M. abscessus.Further analysis of LVX/RFB via Bliss independence model pointed to dose-dependent synergistic interactions in clinically actionable concentrations.Conclusions: IDentif.AI-designed combinations may provide alternative regimen options to current SOC combinations that are often administered with Amikacin, which has been known to induce ototoxicity in patients.Furthermore, IDentif.AI pinpointed 2-drug interactions may also serve as the backbone for the development of other effective 3-and 4-drug combination therapies.The findings in this study suggest that this platform may contribute to NTM-specific drug development.
Tomographic detection of photon pairs produced from high-energy X-rays for the monitoring of radiotherapy dosing
Authors: Qihui Lyu, Ryan Neph, Ke Sheng
Journal: Nature Biomedical Engineering (2022)

Measuring the radiation dose reaching a patient's body is difficult. Here we report a technique for the tomographic reconstruction of the location of photon pairs originating from the annihilation of positron-electron pairs produced by high-energy X-rays travelling through tissue. We used Monte Carlo simulations on pre-recorded data from tissue-mimicking phantoms and from a patient with a brain tumour to show the feasibility of this imaging modality, which we named 'pair-production tomography', for the monitoring of radiotherapy dosing. We simulated three image-reconstruction methods, one applicable to a pencil X-ray beam scanning through a region of interest, and two applicable to the excitation of tissue volumes via broad beams (with temporal resolution sufficient to identify coincident photon pairs via filtered back projection, or with higher temporal resolution sufficient for the estimation of a photon's time-of-flight). In addition to the monitoring of radiotherapy dosing, we show that image contrast resulting from pair-production tomography is highly proportional to the material's atomic number. The technique may thus also allow for element mapping and for soft-tissue differentiation.
Identification of Mechanisms by Which Genetic Susceptibility Loci Influence Systemic Sclerosis Risk Using Functional Genomics in Primary T Cells and Monocytes
Authors: David González‐Serna, Chenfu Shi, Martin Kerick, Jenny Hankinson, James Ding, Amanda McGovern, Mauro Tutino, Gonzalo Villanueva‐Martin, Norberto Ortego‐Centeno, José Luis Callejas, Javier Martin, Gisela Orozco
Journal: Arthritis & Rheumatology (2022)

Systemic sclerosis (SSc) is a complex autoimmune disease with a strong genetic component. However, most of the genes associated with the disease are still unknown because associated variants affect mostly noncoding intergenic elements of the genome. We used functional genomics to translate the genetic findings into a better understanding of the disease.
Annals Graphic Medicine - Dr. Mom: The Thrill of Working in the Hospital Where I Was Born
Authors: Grace E. Farris
Journal: Annals of Internal Medicine (2022)

Web ExclusivesNovember 2022Annals Graphic Medicine - Dr. Mom: The Thrill of Working in the Hospital Where I Was BornFREEGrace E. Farris, MDGrace E. Farris, MDUniversity of Texas, Austin, Texas (G.E.F.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G22-0053 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Grace E. Farris, MDAffiliations: University of Texas, Austin, Texas (G.E.F.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G22-0020.Author/Illustrator Information: Grace E. Farris, MD, is an assistant professor of medicine at Dell Medical School at the University of Texas in Austin, Texas. You can view her work at her website: www.farrisgrace.com.About Dr. Mom: In Dr. Mom, physician and cartoonist Grace Farris examines work–life balance while mothering and doctoring. Dr. Mom appears quarterly in Annals Graphic Medicine at Annals.org.This article was published at Annals.org on 25 October 2022. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics November 2022Volume 175, Issue 11Page: W148-W149 ePublished: 25 October 2022 Issue Published: November 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
ERK inactivation enhances stemness of NSCLC cells via promoting Slug-mediated epithelial-to-mesenchymal transition
Authors: Shurui Cai, Na Li, Xuetao Bai, Lu Liu, Ananya Banerjee, Kousalya Lavudi, Xiaoli Zhang, Jihe Zhao, Monica Venere, Wenrui Duan, Junran Zhang, Meng X. Welliver, Kai He, Qi-En Wang
Journal: Theranostics (2022)

Rationale: The mitogen-activated protein kinase pathway (MAPK) is one of the major cancer-driving pathways found in non-small cell lung cancer (NSCLC) patients. ERK inhibitors (ERKi) have been shown to be effective in NSCLC patients with MAPK pathway mutations. However, like other MAPK inhibitors, ERKi rarely confers complete and durable responses. The mechanism of tumor relapse after ERKi treatment is yet defined. Methods: To best study the mechanism of tumor relapse after ERK inhibitor treatment in NSCLC patients, we treated various NSCLC cell lines and patient-derived xenograft (PDX) with ERK inhibitors and evaluated the enrichment of cancer stem cell (CSC) population. We then performed a Next-generation sequencing (NGS) to identify potential pathways that are responsible for the CSC enrichment. Further, the involvement of specific pathways was examined using molecular and cellular methods. Finally, we investigated the therapeutic benefits of ERKi treatment combined with JAK/STAT pathway inhibitor using cellular and xenograft NSCLC models. Results: We found that ERKi treatment expands the CSC population in NSCLC cells through enhanced epithelial-to-mesenchymal transition (EMT)-mediated cancer cell dedifferentiation. Mechanistically, ERK inactivation induces EMT via pSTAT3-mediated upregulation of Slug, in which, upregulation of miR-204 and downregulation of SPDEF, a transcription repressor of Slug, are involved. Finally, the JAK/STAT pathway inhibitor Ruxolitinib blocks the ERK inactivation-induced EMT and CSC expansion, as well as the tumor progression in xenograft models after ERKi treatment. Conclusions: This study revealed a potential tumor relapse mechanism of NSCLC after ERK inhibition through the unintended activation of the EMT program, ascertained the pSTAT-miR-204-SPDEF-Slug axis, and provided a promising combination inhibitor approach to prevent tumor relapse in patients.
Single-Nucleotide Variants and Epimutations Induce Proteasome Inhibitor Resistance in Multiple Myeloma
Authors: Larissa Haertle, Santiago Barrio, Umair Munawar, Seungbin Han, Xiang Zhou, Michal Simicek, Cornelia Vogt, Marietta Truger, Rafael Alonso Fernandez, Maximilian Steinhardt, Julia Weingart, Renata Snaurova, Silvia Nerreter, Eva Teufel, Andoni Garitano-Trojaola, Matteo Da Viá, Yanira Ruiz-Heredia, Andreas Rosenwald, Niccolò Bolli, Roman Hajek, Peter Raab, Marc S. Raab, Niels Weinhold, Claudia Haferlach, Thomas Haaf, Joaquin Martinez-Lopez, Hermann Einsele, Leo Rasche, K. Martin Kortüm
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Proteasome inhibitors (PI) are the backbone of various treatment regimens in multiple myeloma. We recently described the first in-patient point mutations affecting the 20S subunit PSMB5 underlying PI resistance. Notably, in vivo, the incidence of mutations in PSMB5 and other proteasome encoding genes is too low to explain the development of resistance in most of the affected patients. Thus, additional genetic and epigenetic alterations need to be explored. Experimental Design: We performed DNA methylation profiling by Deep Bisulfite Sequencing in PSMB5, PSMC2, PSMC5, PSMC6, PSMD1, and PSMD5, a subset of proteasome subunits that have hitherto been associated with PI resistance, recruited from our own previous research, the literature, or a meta-analysis on the frequency of somatic mutations. Methylation was followed up on gene expression level and by dual-luciferase reporter assay. The KMS11 cell line served as a model to functionally test the impact of demethylating agents. Results: We identified PSMD5 promoter hypermethylation and subsequent epigenetic gene silencing in 24% of PI refractory patients. Hypermethylation correlated with decreased expression and the regulatory impact of this region was functionally confirmed. In contrast, patients with newly diagnosed multiple myeloma, along with peripheral blood mononuclear cells and CD138+ plasma cells from healthy donors, generally show unmethylated profiles. Conclusions: Under the selective pressure of PI treatment, multiple myeloma cells acquire methylation of the PSMD5 promoter silencing the PSMD5 gene expression. PSMD5 acts as a key orchestrator of proteasome assembly and its downregulation was described to increase the cell's proteolytic capacity. PSMD5 hypermethylation, therefore, represents a novel mechanism of PI tolerance in multiple myeloma.
Near-infrared-II ratiometric fluorescence probes for non-invasive detection and precise navigation surgery of metastatic sentinel lymph nodes
Authors: Mengfei Li, Xue Zheng, Tianyang Han, Shengjie Ma, Yajun Wang, Bin Sun, Jiajun Xu, Xin Wang, Songling Zhang, Shoujun Zhu, Xiaoyuan Chen
Journal: Theranostics (2022)

Sentinel lymph node (SLN) biopsy is the key diagnostic procedure to determine tumor metastasis and treatment plan.Current SLN biopsy has considerable drawbacks in that SLNs (both malignant and normal) must be removed by navigation surgery, followed by a time-consuming pathological examination.The selective, non-invasive, and real-time diagnosis of metastatic status in SLNs is becoming essential.Methods: Here, we design two lanthanide-doped nanoparticles as a pair of NIR-II ratiometric fluorescence probes, one of which is conjugated with tumor-targeting moiety, while the other is conjugated with PEG as an internal reference.The NIR-II ratiometric fluorescence signal (I1060 nm/I1525 nm) from two well-separated channels were used to identify the tumor-draining SLNs.The precise navigation surgery of metastatic SLNs was performed and we further evaluated their surgery outcomes. Results:The NIR-II ratiometric fluorescence facilitates an ideal fluorescence-guided surgery with only resection of tumor-positive SLNs, thereby avoiding unnecessary removal of the normal SLNs.In addition, our system has a time-saving operation procedure and can be performed under the operation light without altering the appearance of surgical settings. Conclusion:The present study enables non-invasive and real-time detection metastatic status in SLNs with high sensitivity and selectivity.Our investigations will provide a new direction for SLN biopsy and substantially improve cancer surgery outcomes.
Morphine use in acute cardiogenic pulmonary oedema: is <scp>MIMO</scp> trial enough to change practice? Letter regarding the article ‘Midazolam versus morphine in acute cardiogenic pulmonary oedema: results of a multicentre, open‐label, randomized controlled trial’
Authors: Tiago Neto Gonçalves, Maria Margarida Andrade
Journal: European Journal of Heart Failure (2022)
Probably, approximately useful frames of mind: A quasi-algorithmic approach
Authors: Mihnea C. Moldoveanu
Journal: Behavioral and Brain Sciences (2022)

Frames for interpreting situations are necessary in the face of time constraints for action and indeterminacy of the "right or optimal thing to do" given multiple objectives but not all frames are equally useful. We need a way of modeling representational frames according to the informational gain of using them and the computational cost of synthesizing a decisive reason for acting from them.
An Approximate Bayesian Computation Approach for Modeling Genome Rearrangements
Authors: Asher Moshe, Elya Wygoda, Noa Ecker, Gil Loewenthal, Oren Avram, Omer Israeli, Einat Hazkani-Covo, Itsik Pe’er, Tal Pupko
Journal: Molecular Biology and Evolution (2022)

The inference of genome rearrangement events has been extensively studied, as they play a major role in molecular evolution. However, probabilistic evolutionary models that explicitly imitate the evolutionary dynamics of such events, as well as methods to infer model parameters, are yet to be fully utilized. Here, we developed a probabilistic approach to infer genome rearrangement rate parameters using an Approximate Bayesian Computation (ABC) framework. We developed two genome rearrangement models, a basic model, which accounts for genomic changes in gene order, and a more sophisticated one which also accounts for changes in chromosome number. We characterized the ABC inference accuracy using simulations and applied our methodology to both prokaryotic and eukaryotic empirical datasets. Knowledge of genome-rearrangement rates can help elucidate their role in evolution as well as help simulate genomes with evolutionary dynamics that reflect empirical genomes.
Identification of a Distinct <scp>Monocyte‐Driven</scp> Signature in Systemic Sclerosis Using Biophysical Phenotyping of Circulating Immune Cells
Authors: Alexandru‐Emil Matei, Markéta Kubánková, Liyan Xu, Andrea‐Hermina Györfi, Evgenia Boxberger, Despina Soteriou, Maria Papava, Julia Prater, Xuezhi Hong, Christina Bergmann, Martin Kräter, Georg Schett, Jochen Guck, Jörg H. W. Distler
Journal: Arthritis & Rheumatology (2022)

Objective Pathologically activated circulating immune cells, including monocytes, play major roles in systemic sclerosis (SSc). Their functional characterization can provide crucial information with direct clinical relevance. However, tools for the evaluation of pathologic immune cell activation and, in general, of clinical outcomes in SSc are scarce. Biophysical phenotyping (including characterization of cell mechanics and morphology) provides access to a novel, mostly unexplored layer of information regarding pathophysiologic immune cell activation. We hypothesized that the biophysical phenotyping of circulating immune cells, reflecting their pathologic activation, can be used as a clinical tool for the evaluation and risk stratification of patients with SSc. Methods We performed biophysical phenotyping of circulating immune cells by real‐time fluorescence and deformability cytometry (RT‐FDC) in 63 SSc patients, 59 rheumatoid arthritis (RA) patients, 28 antineutrophil cytoplasmic antibody–associated vasculitis (AAV) patients, and 22 age‐ and sex‐matched healthy donors. Results We identified a specific signature of biophysical properties of circulating immune cells in SSc patients that was mainly driven by monocytes. Since it is absent in RA and AAV, this signature reflects an SSc‐specific monocyte activation rather than general inflammation. The biophysical properties of monocytes indicate current disease activity, the extent of skin or lung fibrosis, and the severity of manifestations of microvascular damage, as well as the risk of disease progression in SSc patients. Conclusion Changes in the biophysical properties of circulating immune cells reflect their pathologic activation in SSc patients and are associated with clinical outcomes. As a high‐throughput approach that requires minimal preparations, RT‐FDC–based biophysical phenotyping of monocytes can serve as a tool for the evaluation and risk stratification of patients with SSc.
Effector Memory–Expressing CD45RA (TEMRA) CD8+ T Cells from Kidney Transplant Recipients Exhibit Enhanced Purinergic P2X4 Receptor–Dependent Proinflammatory and Migratory Responses
Authors: Tra-My Doan Ngoc, Gaëlle Tilly, Richard Danger, Orianne Bonizec, Christophe Masset, Pierrick Guérif, Sarah Bruneau, Alexandre Glemain, Jean Harb, Marion Cadoux, Anaïs Vivet, Hoa Le Mai, Alexandra Garcia, David Laplaud, Roland Liblau, Magali Giral, Stéphanie Blandin, Magalie Feyeux, Laurence Dubreuil, Claire Pecqueur, Matthew Cyr, Weiming Ni, Sophie Brouard, Nicolas Degauque
Journal: Journal of the American Society of Nephrology (2022)

The mechanisms regulating CD8
Specificity of oligonucleotide gene therapy (OGT) agents
Authors: Daria D. Nedorezova, Mikhail V. Dubovichenko, Ekaterina P. Belyaeva, Ekaterina D. Grigorieva, Arina V. Peresadina, Dmitry M. Kolpashchikov
Journal: Theranostics (2022)

Oligonucleotide gene therapy (OGT) agents (e. g. antisense, deoxyribozymes, siRNA and CRISPR/Cas) are promising therapeutic tools.Despite extensive efforts, only few OGT drugs have been approved for clinical use.Besides the problem of efficient delivery to targeted cells, hybridization specificity is a potential limitation of OGT agents.To ensure tight binding, a typical OGT agent hybridizes to the stretch of 15-25 nucleotides of a unique targeted sequence.However, hybrids of such lengths tolerate one or more mismatches under physiological conditions, the problem known as the affinity/specificity dilemma.Here, we assess the scale of this problem by analyzing OGT hybridization-dependent off-target effects (HD OTE) in vitro, in animal models and clinical studies.All OGT agents except deoxyribozymes exhibit HD OTE in vitro, with most thorough evidence of poor specificity reported for siRNA and CRISPR/Cas9.Notably, siRNA suppress non-targeted genes due to (1) the partial complementarity to mRNA 3'-untranslated regions (3'-UTR), and (2) the antisense activity of the sense strand.CRISPR/Cas9 system can cause hundreds of non-intended dsDNA breaks due to low specificity of the guide RNA, which can limit therapeutic applications of CRISPR/Cas9 by ex-vivo formats.Contribution of this effects to the observed in vivo toxicity of OGT agents is unclear and requires further investigation.Locked or peptide nucleic acids improve OGT nuclease resistance but not specificity.Approaches that use RNA marker dependent (conditional) activation of OGT agents may improve specificity but require additional validation in cell culture and in vivo.
Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer
Authors: Xiaomeng Tang, Dan Li, Yongwei Gu, Yunan Zhao, Aixue Li, Fu Qi, Jiyong Liu
Journal: Theranostics (2022)

Digestive system cancer is the most common cause of cancer death in the world. Although cancer treatment options are increasingly diversified, the mortality rate of malignant cancer of the digestive system remains high. Therefore, it is necessary to explore effective cancer treatment methods. Recently, biomimetic nanoparticle delivery systems based on natural cells that organically integrate the low immunogenicity, high biocompatibility, cancer targeting, and controllable, versatile functionality of smart nanocarrier design with natural cells have been expected to break through the bottleneck of tumor targeted therapy. In this review, we focus on the dynamic changes and complex cellular communications that occur
Multiomics study of nonalcoholic fatty liver disease
Authors: Gardar Sveinbjornsson, Magnus O. Ulfarsson, Rosa B. Thorolfsdottir, Benedikt A. Jonsson, Eythor Einarsson, Gylfi Gunnlaugsson, Solvi Rognvaldsson, David O. Arnar, Magnus Baldvinsson, Ragnar G. Bjarnason, Thjodbjorg Eiriksdottir, Christian Erikstrup, Egil Ferkingstad, Gisli H. Halldorsson, Hannes Helgason, Anna Helgadottir, Lotte Hindhede, Grimur Hjorleifsson, David Jones, Kirk U. Knowlton, Sigrun H. Lund, Pall Melsted, Kristjan Norland, Isleifur Olafsson, Sigurdur Olafsson, Gudjon R. Oskarsson, Sisse Rye Ostrowski, Ole Birger Pedersen, Auðunn S. Snaebjarnarson, Emil Sigurdsson, Valgerdur Steinthorsdottir, Michael Schwinn, Gudmundur Thorgeirsson, Gudmar Thorleifsson, Ingileif Jonsdottir, Henning Bundgaard, Lincoln Nadauld, Einar S. Bjornsson, Ingrid C. Rulifson, Thorunn Rafnar, Gudmundur L. Norddahl, Unnur Thorsteinsdottir, Patrick Sulem, Daniel F. Gudbjartsson, Hilma Holm, Kari Stefansson
Journal: Nature Genetics (2022)

Nonalcoholic fatty liver (NAFL) and its sequelae are growing health problems. We performed a genome-wide association study of NAFL, cirrhosis and hepatocellular carcinoma, and integrated the findings with expression and proteomic data. For NAFL, we utilized 9,491 clinical cases and proton density fat fraction extracted from 36,116 liver magnetic resonance images. We identified 18 sequence variants associated with NAFL and 4 with cirrhosis, and found rare, protective, predicted loss-of-function variants in MTARC1 and GPAM, underscoring them as potential drug targets. We leveraged messenger RNA expression, splicing and predicted coding effects to identify 16 putative causal genes, of which many are implicated in lipid metabolism. We analyzed levels of 4,907 plasma proteins in 35,559 Icelanders and 1,459 proteins in 47,151 UK Biobank participants, identifying multiple proteins involved in disease pathogenesis. We show that proteomics can discriminate between NAFL and cirrhosis. The present study provides insights into the development of noninvasive evaluation of NAFL and new therapeutic options.
The ultrasonographic pseudo–double contour sign in calcium pyrophosphate deposition disease: an anatomic explanation and how to distinguish it from gout
Authors: Georgios Filippou, Maribel Miguel‐Pérez, Luis Coronel, Silvia Sirotti, Giovanni Pacini, Anna Scanu, David Bong, Ingrid Möller
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Video S1: Supplementary Video Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
The received view of framing
Authors: Paul Weirich
Journal: Behavioral and Brain Sciences (2022)

Abstract The received view of framing has multiple interpretations. I flesh out an interpretation that is more open-minded about framing effects than the extensionality principle that Bermúdez formulates. My interpretation attends to the difference between preferences held all things considered and preferences held putting aside some considerations. It also makes room for decision principles that handle cases without a complete all-things-considered preference-ranking of options.